PMID- 35635307 OWN - NLM STAT- MEDLINE DCOM- 20220602 LR - 20230907 IS - 1521-0464 (Electronic) IS - 1071-7544 (Print) IS - 1071-7544 (Linking) VI - 29 IP - 1 DP - 2022 Dec TI - Icaritin-loaded PLGA nanoparticles activate immunogenic cell death and facilitate tumor recruitment in mice with gastric cancer. PG - 1712-1725 LID - 10.1080/10717544.2022.2079769 [doi] AB - This study aimed to explore the anti-tumor effect of icaritin loading poly (lactic-co-glycolic acid) nanoparticles (refer to PLGA@Icaritin NPs) on gastric cancer (GC) cells. Transmission Electron Microscope (TEM), size distribution, zeta potential, drug-loading capability, and other physicochemical characteristics of PLGA@Icaritin NPs were carried out. Furthermore, flow cytometry, confocal laser scanning microscope (CLSM), Cell Counting Kit-8 (CCK-8), Transwell, Elisa assay and Balb/c mice were applied to explore the cellular uptake, anti-proliferation, anti-metastasis, immune response activation effects, and related anti-tumor mechanism of PLGA@Icaritin NPs in vitro and in vivo. PLGA@Icaritin NPs showed spherical shape, with appropriate particle sizes and well drug loading and releasing capacities. Flow cytometry and CLSM results indicated that PLGA@Icaritin could efficiently enter into GC cells. CCK-8 proved that PLGA@Icaritin NPs dramatically suppressed cell growth, induced Lactic dehydrogenase (LDH) leakage, arrested more GC cells at G2 phase, and inhibited the invasion and metastasis of GC cells, compared to free icaritin. In addition, PLGA@Icaritin could help generate dozens of reactive oxygen species (ROS) within GC cells, following by significant mitochondrial membrane potentials (MMPs) loss and excessive production of oxidative-mitochondrial DNA (Ox-mitoDNA). Since that, Ox-mitoDNA further activated the releasing of damage associated molecular pattern molecules (DAMPs), and finally led to immunogenic cell death (ICD). Our in vivo data also elaborated that PLGA@Icaritin exerted a powerful inhibitory effect ( approximately 80%), compared to free icaritin ( approximately 60%). Most importantly, our results demonstrated that PLGA@Icaritin could activate the anti-tumor immunity via recruitment of infiltrating CD4+ cells, CD8+ T cells and increased secretion of cytokine immune factors, including interferon-gamma (IFN-gamma) tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1).(++) Our findings validate that the successful design of PLGA@Icaritin, which can effectively active ICD and facilitate tumor recruitment in GC through inducing mitoDNA oxidative damage. FAU - Xiao, Yao AU - Xiao Y AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Yao, Wenxia AU - Yao W AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Lin, Mingzhen AU - Lin M AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Huang, Wei AU - Huang W AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Li, Ben AU - Li B AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Peng, Bin AU - Peng B AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Ma, Qinhai AU - Ma Q AD - State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510062, China. FAU - Zhou, Xinke AU - Zhou X AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. FAU - Liang, Min AU - Liang M AD - Department of Oncology, Innovation centre for Advanced Interdisciplinary Medicine, Guangzhou Key Laboratory of Enhanced Recovery after Abdominal Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510700, China. LA - eng PT - Journal Article PL - England TA - Drug Deliv JT - Drug delivery JID - 9417471 RN - 0 (Flavonoids) RN - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer) RN - 26009-03-0 (Polyglycolic Acid) RN - 33X04XA5AT (Lactic Acid) RN - UFE666UELY (icaritin) SB - IM MH - Animals MH - Flavonoids MH - Immunogenic Cell Death MH - Lactic Acid/chemistry MH - Mice MH - *Nanoparticles/chemistry MH - Polyglycolic Acid/chemistry MH - Polylactic Acid-Polyglycolic Acid Copolymer MH - *Stomach Neoplasms/drug therapy PMC - PMC9176696 OTO - NOTNLM OT - Icaritin OT - Immunogenic cell death (ICD) OT - Mitochondrial oxidative damage OT - poly (lactic-co-glycolic acid) (PLGA) COIS- No potential conflict of interest was reported by the author(s). EDAT- 2022/06/01 06:00 MHDA- 2022/06/03 06:00 PMCR- 2022/05/30 CRDT- 2022/05/31 12:22 PHST- 2022/05/31 12:22 [entrez] PHST- 2022/06/01 06:00 [pubmed] PHST- 2022/06/03 06:00 [medline] PHST- 2022/05/30 00:00 [pmc-release] AID - 2079769 [pii] AID - 10.1080/10717544.2022.2079769 [doi] PST - ppublish SO - Drug Deliv. 2022 Dec;29(1):1712-1725. doi: 10.1080/10717544.2022.2079769.